Project Summary Heterozygous deletion of neurexin-1 (NRXN1), a presynaptic cell adhesion molecule, is strongly associated with neuropsychiatric disorders and psychosis. NRXN1 is highly alternatively spliced and recently a role for these splice isoforms in neuronal identity has been suggested; however, NRXN1 isoforms have not been characterized in human neurons. Animal models of NRXN1 deletion display deficits in behavior and neuronal activity. However, animal models cannot recapitulate the effect of myriad patient-specific deletions in the context of other risk variants within a patient?s genome; together, these effects likely influence the variable penetrance of NRXN1 deletions, which confer a diverse set of clinical diagnoses. Using hiPSC-neurons derived from a rare cohort of four psychosis patients carrying NRXN1 deletions, this proposal will investigate the casual contribution of these deletions on gene expression, alternative splicing and neuronal phenotypes in excitatory hiPSC-neurons. There are three aims: the first is identify differences in alternative splicing in NRXN1 deletion hiPSC-neurons, the second is to restore isoform deficiencies and manipulate NRXN1 expression in hiPSC-neurons, and the third is to establish the functional significance of NRXN1 deletion in hiPSC-neurons. My hypothesis is that excitatory hiPSC-neurons derived from four psychosis patients will exhibit differential expression of NRXN1 isoforms which are crucial for proper neuronal activity and morphology. We include strong preliminary data demonstrating the feasibility of our proposal; moreover, we have already observed that NRXN1 hiPSC-neurons express both wildtype and deleted allele variants. Our hope is that these experiments will improve our understanding of the molecular mechanisms underlying genetic risk for neuropsychiatric disorders.